Quantitative Genetics of CTCF Binding Reveal Local Sequence Effects and Different Modes of X-Chromosome Association
We have systematically measured the effect of normal genetic variation present in a human population on the binding of a specific chromatin protein (CTCF) to DNA by measuring its binding in 51 human cell lines. We observed a large number of changes in protein binding that we can confidently attribute to genetic effects. The corresponding genetic changes are often clustered around the binding motif for CTCF, but only a minority are actually within the motif. Unexpectedly, we also find that at most binding sites on the X chromosome, CTCF binding occurs equally on both the X chromosomes in females at the same level as on the single X chromosome in males. This finding suggests that in general, CTCF binding is not subject to global dosage compensation, the process which equalizes gene expression levels from the two female X chromosomes and the single male X.
Vyšlo v časopise:
Quantitative Genetics of CTCF Binding Reveal Local Sequence Effects and Different Modes of X-Chromosome Association. PLoS Genet 10(11): e32767. doi:10.1371/journal.pgen.1004798
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1004798
Souhrn
We have systematically measured the effect of normal genetic variation present in a human population on the binding of a specific chromatin protein (CTCF) to DNA by measuring its binding in 51 human cell lines. We observed a large number of changes in protein binding that we can confidently attribute to genetic effects. The corresponding genetic changes are often clustered around the binding motif for CTCF, but only a minority are actually within the motif. Unexpectedly, we also find that at most binding sites on the X chromosome, CTCF binding occurs equally on both the X chromosomes in females at the same level as on the single X chromosome in males. This finding suggests that in general, CTCF binding is not subject to global dosage compensation, the process which equalizes gene expression levels from the two female X chromosomes and the single male X.
Zdroje
1. HindorffLA, SethupathyP, JunkinsHA, RamosEM, MehtaJP, et al. (2009) Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci U S A 106: 9362–9367.
2. AbecasisGR, AltshulerD, AutonA, BrooksLD, DurbinRM, et al. (2010) A map of human genome variation from population-scale sequencing. Nature 467: 1061–1073.
3. BarskiA, CuddapahS, CuiK, RohTY, SchonesDE, et al. (2007) High-resolution profiling of histone methylations in the human genome. Cell 129: 823–837.
4. HesselberthJR, ChenX, ZhangZ, SaboPJ, SandstromR, et al. (2009) Global mapping of protein-DNA interactions in vivo by digital genomic footprinting. Nat Methods 6: 283–289.
5. BoyleAP, DavisS, ShulhaHP, MeltzerP, MarguliesEH, et al. (2008) High-resolution mapping and characterization of open chromatin across the genome. Cell 132: 311–322.
6. JohnS, SaboPJ, ThurmanRE, SungMH, BiddieSC, et al. (2011) Chromatin accessibility pre-determines glucocorticoid receptor binding patterns. Nat Genet 43: 264–268.
7. SongL, ZhangZ, GrasfederLL, BoyleAP, GiresiPG, et al. (2011) Open chromatin defined by DNaseI and FAIRE identifies regulatory elements that shape cell-type identity. Genome Res 21: 1757–1767.
8. McDaniellR, LeeBK, SongL, LiuZ, BoyleAP, et al. (2010) Heritable individual-specific and allele-specific chromatin signatures in humans. Science 328: 235–239.
9. KasowskiM, GrubertF, HeffelfingerC, HariharanM, AsabereA, et al. (2010) Variation in transcription factor binding among humans. Science 328: 232–235.
10. ReddyTE, GertzJ, PauliF, KuceraKS, VarleyKE, et al. (2012) Effects of sequence variation on differential allelic transcription factor occupancy and gene expression. Genome Res 22: 860–869.
11. HeinzS, RomanoskiCE, BennerC, AllisonKA, KaikkonenMU, et al. (2013) Effect of natural genetic variation on enhancer selection and function. Nature 503: 487–492.
12. MauranoMT, WangH, KutyavinT, StamatoyannopoulosJA (2012) Widespread site-dependent buffering of human regulatory polymorphism. PLoS Genet 8: e1002599.
13. StefflovaK, ThybertD, WilsonMD, StreeterI, AleksicJ, et al. (2013) Cooperativity and rapid evolution of cobound transcription factors in closely related mammals. Cell 154: 530–540.
14. StrangerBE, NicaAC, ForrestMS, DimasA, BirdCP, et al. (2007) Population genomics of human gene expression. Nat Genet 39: 1217–1224.
15. SpielmanRS, BastoneLA, BurdickJT, MorleyM, EwensWJ, et al. (2007) Common genetic variants account for differences in gene expression among ethnic groups. Nat Genet 39: 226–231.
16. PickrellJK, MarioniJC, PaiAA, DegnerJF, EngelhardtBE, et al. (2010) Understanding mechanisms underlying human gene expression variation with RNA sequencing. Nature 464: 768–772.
17. DegnerJF, PaiAA, Pique-RegiR, VeyrierasJB, GaffneyDJ, et al. (2012) DNase I sensitivity QTLs are a major determinant of human expression variation. Nature 482: 390–394.
18. LeeBK, IyerVR (2012) Genome-wide studies of CCCTC-binding factor (CTCF) and cohesin provide insight into chromatin structure and regulation. J Biol Chem 287: 30906–30913.
19. MerkenschlagerM, OdomDT (2013) CTCF and cohesin: linking gene regulatory elements with their targets. Cell 152: 1285–1297.
20. YusufzaiTM, TagamiH, NakataniY, FelsenfeldG (2004) CTCF tethers an insulator to subnuclear sites, suggesting shared insulator mechanisms across species. Mol Cell 13: 291–298.
21. SplinterE, HeathH, KoorenJ, PalstraRJ, KlousP, et al. (2006) CTCF mediates long-range chromatin looping and local histone modification in the beta-globin locus. Genes Dev 20: 2349–2354.
22. SopherBL, LaddPD, PinedaVV, LibbyRT, SunkinSM, et al. (2011) CTCF regulates ataxin-7 expression through promotion of a convergently transcribed, antisense noncoding RNA. Neuron 70: 1071–1084.
23. BellAC, FelsenfeldG (2000) Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 405: 482–485.
24. BellAC, WestAG, FelsenfeldG (1999) The protein CTCF is required for the enhancer blocking activity of vertebrate insulators. Cell 98: 387–396.
25. van de NobelenS, Rosa-GarridoM, LeersJ, HeathH, SoochitW, et al. (2010) CTCF regulates the local epigenetic state of ribosomal DNA repeats. Epigenetics Chromatin 3: 19.
26. StedmanW, KangH, LinS, KissilJL, BartolomeiMS, et al. (2008) Cohesins localize with CTCF at the KSHV latency control region and at cellular c-myc and H19/Igf2 insulators. EMBO J 27: 654–666.
27. SchmidtD, SchwaliePC, Ross-InnesCS, HurtadoA, BrownGD, et al. (2010) A CTCF-independent role for cohesin in tissue-specific transcription. Genome Res 20: 578–588.
28. SchmidtD, WilsonMD, BallesterB, SchwaliePC, BrownGD, et al. (2010) Five-vertebrate ChIP-seq reveals the evolutionary dynamics of transcription factor binding. Science 328: 1036–1040.
29. PhillipsJE, CorcesVG (2009) CTCF: master weaver of the genome. Cell 137: 1194–1211.
30. CuddapahS, JothiR, SchonesDE, RohTY, CuiK, et al. (2009) Global analysis of the insulator binding protein CTCF in chromatin barrier regions reveals demarcation of active and repressive domains. Genome Res 19: 24–32.
31. MontgomerySB, SammethM, Gutierrez-ArcelusM, LachRP, IngleC, et al. (2010) Transcriptome genetics using second generation sequencing in a Caucasian population. Nature 464: 773–777.
32. HeardE, DistecheCM (2006) Dosage compensation in mammals: fine-tuning the expression of the X chromosome. Genes Dev 20: 1848–1867.
33. LeeBK, BhingeAA, BattenhouseA, McDaniellRM, LiuZ, et al. (2012) Cell-type specific and combinatorial usage of diverse transcription factors revealed by genome-wide binding studies in multiple human cells. Genome Res 22: 9–24.
34. StoreyJD, TibshiraniR (2003) Statistical significance for genomewide studies. Proc Natl Acad Sci U S A 100: 9440–9445.
35. LappalainenT, SammethM, FriedlanderMR, t HoenPA, MonlongJ, et al. (2013) Transcriptome and genome sequencing uncovers functional variation in humans. Nature 501: 506–511.
36. CarrelL, WillardHF (2005) X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434: 400–404.
37. ENCODE_Project_Consortium (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489: 57–74.
38. HorakovaAH, MoseleySC, McLaughlinCR, TremblayDC, ChadwickBP (2012) The macrosatellite DXZ4 mediates CTCF-dependent long-range intrachromosomal interactions on the human inactive X chromosome. Hum Mol Genet 21: 4367–4377.
39. JeonY, LeeJT (2011) YY1 tethers Xist RNA to the inactive X nucleation center. Cell 146: 119–133.
40. McVickerG, van de GeijnB, DegnerJF, CainCE, BanovichNE, et al. (2013) Identification of genetic variants that affect histone modifications in human cells. Science 342: 747–749.
41. SchmidtD, SchwaliePC, WilsonMD, BallesterB, GoncalvesA, et al. (2012) Waves of retrotransposon expansion remodel genome organization and CTCF binding in multiple mammalian lineages. Cell 148: 335–348.
42. ChaoW, HuynhKD, SpencerRJ, DavidowLS, LeeJT (2002) CTCF, a candidate trans-acting factor for X-inactivation choice. Science 295: 345–347.
43. JeonY, SarmaK, LeeJT (2012) New and Xisting regulatory mechanisms of X chromosome inactivation. Curr Opin Genet Dev 22: 62–71.
44. KilpinenH, WaszakSM, GschwindAR, RaghavSK, WitwickiRM, et al. (2013) Coordinated effects of sequence variation on DNA binding, chromatin structure, and transcription. Science 342: 744–747.
45. KasowskiM, Kyriazopoulou-PanagiotopoulouS, GrubertF, ZauggJB, KundajeA, et al. (2013) Extensive variation in chromatin states across humans. Science 342: 750–752.
46. LiH, DurbinR (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25: 1754–1760.
47. StrangerBE, MontgomerySB, DimasAS, PartsL, StegleO, et al. (2012) Patterns of cis regulatory variation in diverse human populations. PLoS Genet 8: e1002639.
48. LiH, HandsakerB, WysokerA, FennellT, RuanJ, et al. (2009) The Sequence Alignment/Map format and SAMtools. Bioinformatics 25: 2078–2079.
49. BrowningBL, YuZ (2009) Simultaneous genotype calling and haplotype phasing improves genotype accuracy and reduces false-positive associations for genome-wide association studies. Am J Hum Genet 85: 847–861.
50. HowieBN, DonnellyP, MarchiniJ (2009) A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet 5: e1000529.
51. ShivaswamyS, BhingeA, ZhaoY, JonesS, HirstM, et al. (2008) Dynamic remodeling of individual nucleosomes across a eukaryotic genome in response to transcriptional perturbation. PLoS Biol 6: e65.
52. BenjaminiY, HochbergY (1995) Controlling the False Discovery Rate - a Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society Series B-Methodological 57: 289–300.
53. QuinlanAR, HallIM (2010) BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26: 841–842.
54. GrantCE, BaileyTL, NobleWS (2011) FIMO: scanning for occurrences of a given motif. Bioinformatics 27: 1017–1018.
55. BaileyTL, BodenM, BuskeFA, FrithM, GrantCE, et al. (2009) MEME SUITE: tools for motif discovery and searching. Nucleic Acids Res 37: W202–208.
56. SubramanianA, TamayoP, MoothaVK, MukherjeeS, EbertBL, et al. (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102: 15545–15550.
57. JeeJ, RozowskyJ, YipKY, LochovskyL, BjornsonR, et al. (2011) ACT: aggregation and correlation toolbox for analyses of genome tracks. Bioinformatics 27: 1152–1154.
58. GribbleSM, WisemanFK, ClaytonS, PrigmoreE, LangleyE, et al. (2013) Massively parallel sequencing reveals the complex structure of an irradiated human chromosome on a mouse background in the Tc1 model of Down syndrome. PLoS One 8: e60482.
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
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